604
Essential Hypertension and
Histocompatibility Antigens
A Linkage Study
M. Gerbase-DeLima, J.J.G. DeLima, L.B. Persoli, H. Beraardes Silva,
M. Marcondes, and G. Bellotti
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
It is well established that genetic and environmental factors are involved in the etiology of
essential hypertension. The presence of genes predisposing to essential hypertension in the
human leukocyte antigen (HLA) complex is controversial because studies of an association
between HLA antigens and essential hypertension have failed to yield consistent results. Our
aim in the present study was to further investigate this issue through the method of linkage
analysis. Analysis of 96 hypertensive siblings distributed in 31 families indicated a significant
distortion (p=0.0009) of the normal segregation pattern of inheritance of HLA haplotypes.
Thus, our data indicate that at least one of the genes responsible for genetic predisposition to
essential hypertension is located very near or within the HLA complex. (Hypertension
1989;14:604-609)
T
here is convincing evidence that essential
hypertension is fundamentally a genetic disease, most likely polygenic in nature, in
which environmental factors also play an important
role.1-5 The relative importance of genetic and
environmental factors depends, to some extent, on
the degree of heterogeneity of these variables in a
given population. For instance, if among members
within a population there are extreme differences in
salt intake, this factor would tend to dominate. If
environmental conditions are more homogeneous,
as it is believed occurs in a normal situation, genetic
determinants should predominate.6 The familial
aggregation of essential hypertension7-9 and the
high concordance rates of blood pressure among
first-degree relatives have been extensively reported
and represent a strong argument in favor of the
genetic control of blood pressure. Monozygotic
twins show the highest correlation coefficient (r) for
blood pressure (r around 0.5).10-12 Significant correlations, although of a lesser degree (r around 0.25)
have been reported for dizygotic twins, siblings,
and parent-offspring comparisons.13-16 The high con-
From the Escola Paulista de Medicina and Institute do Coracfio, Hospital das Clfnicas, Faculdade de Medicina, Universidade de S5o Paulo, Sao Paulo, Brazil.
Supported by Consclho National de Desenvotvimento Cientffico E Tecnol6gico (403195/87.0-BM) and Fundacao de Amparo
a Pesquisa do Estado de Sao Paulo.
Address for correspondence: Maria Gerbase de Lima, Rua
Pirandello, 709 04623 Sfio Paulo, SP, Brazil.
Received January 9, 1989; accepted in revised form June 26,
1989.
cordance rate of blood pressure in monozygotic
twins, whether living in the same environment or
not, and the lack of correlation of blood pressure
between parents and adopted children and between
natural and adopted siblings, further indicate that
genetic rather than shared environmental factors
are primarily responsible for the blood pressure
familial aggregation.17'18
Several studies have appeared concerning human
leukocyte antigens (HLA) as markers for essential
hypertension.19-29 As shown in a summary of published results (Table 1), different authors have
reported a tendency for increased frequency of
certain HLA-A and B antigens among patients with
essential hypertension. HLA-DR antigens were
investigated in a single study.29 Although the great
majority of differences in HLA antigen frequencies
between patient and control groups do not reach
statistical significance when the/? value is corrected
for the number of antigens tested,30 it is nevertheless interesting that some antigens, such as B12,
B15, and B18, were found more frequently in hypertensive patients from different populations.
The aim of the present study was to investigate
the genes predisposing to essential hypertension in
the HLA complex by the method of linkage analysis. The HLA region can be studied as a single unit
with this approach because this method takes into
account the pattern of inheritance of HLA haplotypes. A distortion in the normal pattern of segregation in affected siblings is an indication of genes in
the HLA complex predisposing to the disease.30-31
Gerbase-DeLima et al Essential Hypertension and HLA
TABLE 1.
605
Summary of Results from Association Studies of HLA Antigens and Essential Hypertension
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References
Patel and Johnson19
Shkhvatsabaya et al20
Low et al21
Gualde et al22
Gelsthorpe et al23
Patel and Johnson1'
Otero et al24
Kristensen et al25
Shkhvatsabaya et al20
Otero et al24
Kristensen et al25
Kristensen et al26
Gudbrandsson et al27
Gualde et al22
Merrier and Jouve28
Merrier and Jouve28
Sengar et al29
Shkhvatsabaya et al20
Otero et al24
Sengar et al29
Race/
country
B/USA
C/Russia
C/Sweden
C/France
CTEngland
B/USA
C/Spain
CVDenmark
C/Russia
C/Spain
CTDenmarkf
QDenmarkt
C7Sweden§
C/France
CFrance
C/France
C/Canada
ORussia
CVSpain
C/Canada
HLA
Antigen frequency (%)
Patients
Controls
/W<
0.02
0.05
All
10
2
All
21
10
B8
41
26
NS
B8
29
12
B12
41
28
B12
35
17
B12
37
27
B21
6
2
B13
19
8
B15
3
6
B15
38
19
B15
50
19
B15
42
23
0.001*
0.02
0.005
0.02
0.02
0.05
0.05
0.002*
0.005
0.07
B15
16
10
NS
B15
16
9
NS
B18
23
10
B18
15
7
B22
11
B22
5
3
1
DR7
34
21
0.05
0.05
0.01
0.001*
0.05
HLA, human leukocyte antigen; p^^, unconnected p value; C, Caucasian; B, Black.
*p<0.05 after correction for the number of antigens tested.
tPatients with family history of essential hypertension.
^Patients with essential hypertension and cerebral events.
§Patients with malignant essential hypertension and family history.
The advantages of linkage analysis over the association method is that genes predisposing to the disease
may be detected even when they are not known HLA
genes or are not in linkage disequilibrium with known
HLA genes. In addition, familial studies tend to
minimize the heterogeneity of environmental factors
that could influence blood pressure.
Subjects and Methods
Selection of Families
Blood pressure and HLA antigens were determined in 166 members of 31 families; each family
had at least two siblings with essential hypertension. The criteria for classification of an individual
as hypertensive were systolic blood pressure equal
to or higher than 160 mm Hg or diastolic blood
pressure equal to or higher than 95 mm Hg (average
of at least two determinations on separate occasions). In all hypertensive individuals, we excluded
malignant or secondary hypertension, as well as
systemic disease. All probands and family members
were seen by one of us (J.J.G.L.) at the Instituto do
Coracao, Faculdade de Medicina, Universidade de
Sao Paulo. The probands comprised 19-42-year-old
individuals (19 men and 12 women, mean
weight/height2 index 24.8) who were being treated
with antihypertensive drugs. They were asked to
contact all their first-degree relatives for examination. The selection of families for inclusion in our
study was based solely on the existence of at least
one affected sib of the proband. The age of the
siblings with essential hypertension varied from 17
to 52 years (mean age 35.0 years); 36 were men and
29 were women; the mean weight/height2 index was
24.9, and the mean systolic and diastolic blood
pressure were 152 and 106 mm Hg, respectively.
Eighteen families were classified as Brazilian Caucasoid, 12 as Negroid, and one was of Japanese
ancestry. The mean number of children in the
Caucasoid and Negroid families was 4.5 and 5.5,
respectively, and the mean number of hypertensive
siblings in the Caucasoid and Negroid famines was
2.5 and 3.8, respectively. The number of affected
siblings in each family was two, three, four, five,
and seven siblings in 11, 10, eight, one, and one
families, respectively. In eight families, both the
parents were known to be hypertensive; in one,
only one of the parents had essential hypertension;
in 10, one parent had essential hypertension but the
other parent was not available for examination, and
in 12 families, both parents were not available for
examination. In 67% of the Caucasoid families and
in 50% of the Negroid families, at least one parent
was known to have essential hypertension.
Human Leukocyte Antigen Typing
HLA antigens were determined with the standard
complement-dependent microlymphocytotoxicity
606
Hypertension
Vol 14, No 6, December 1989
method,32 using both local and international antiHLA sera. HLA-A and B antigens were determined
in 166 individuals from the 31 families studied,
including 96 hypertensive siblings, 25 parents, and
45 normotensive siblings. HLA-DR antigens were
typed only in the probands.
Statistical Analysis
For the statistical analysis in the linkage study, we
used the method of sib analysis for multiplex family
cases as described by Green and Woodrow.33 HLAA, B, and DR frequencies observed in the Caucasoid
probands were compared (Fisher's test) with those
determined in a local Caucasoid control population.34
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Results
As the first step in the study of cosegregation of
essential hypertension and HLA genes, we determined the HLA haplotypes within each family,
based on the HLA typing available, from both
normal and hypertensive individuals. In 21 families,
the four parental HLA haplotypes could be deduced;
in seven families, three parental HLA haplotypes,
and in three families, two parental HLA haplotypes
could be deduced. In none of the families were
there any known HLA haplotypes in common
between the parents. The possibility of misassignment of genotypes of the siblings because of HLA
haplotype sharing between the parents or by homozygosity was considered virtually negligible because
of the polymorphism in the HLA system shown by
our,34 as well as by other, populations. We also did
not consider the possibility of recombination
between the HLA-A and B loci because this is
estimated to be less than 1%. In Figure 1, we
present examples of pedigree diagrams from two of
the families studied. In family no. 19, the two
hypertensive siblings share two HLA haplotypes
(haplotype a, inherited from the father, and haplotype c, inherited from the mother); in family no. 21,
the three hypertensive siblings share one HLA
haplotype (haplotype c, inherited from the hypertensive mother). The paternal and maternal HLA
haplotypes observed in all the hypertensive siblings
studied are indicated in Table 2, where it can be
seen that in 20 of 31 families all the hypertensive
siblings shared at least one HLA haplotype. At least
one shared HLA haplotype was observed in all
affected siblings in 15 of 18 Caucasoid families and
in five of the 12 Negroid families studied. It should
be noted, however, that in five Negroid families
with at least four affected siblings there was a
tendency for HLA haplotype sharing, although not
all of the siblings shared one HLA haplotype (Table
2, families no. 3,4,9,10, and 27).
The statistical analysis, according to Green and
Woodrow,33 is presented in Table 3. The number of
observed (N=97) and expected (mean number=86.1)
HLA haplotypes in common among hypertensive
siblings was statistically different (/?=0.0009), thus
A. FAMILY *
19
• AS B S
• AS BI2
A* BX
••)
6^^
A2
a
A X B2I
a 4
B3S
BX
e
B. FAMILY *
A* BSS
A S B2I
a 4
A*BS
AS2 B2I
a •
A» B3B
A2 BX
a c
21
ASO B l » \
•
(» AX BS 1
• •
AX
A2 BS
BIT
^AX
A2 BS
BIT
be
be
D
O
NORMOTEMSIVE
•
•
HYPERTENSIVE
0
DECEASED
0 O
FIGURE
n
AS B S
A12 B2I
a 4
UNAVALABLE
1
1
B«
ASO
A2 BIT
o c
__^^
^ ^
A2 BIT c
Al BS 4
6 6
UOtm
Al BS
0 a
/
ASO BIS
Al BS
0 d
PROflAND
obo«'HLA HAPLOTYPES
( ) 'DEDUCED HLA HAPUOTYPCS
X ilMXNMM
AimCfM
1. Pedigree diagrams of two of the families
studied.
indicating a distortion in the HLA haplotype segregation pattern among hypertensive siblings.
The HLA antigen frequencies derived from the
probands of the 18 Caucasoid families were compared with the ones obtained in a local Caucasoid
control population, and we observed a tendency
(uncorrected p<0.05, corrected /?>0.05) for an
increased frequency of the antigens HLA-DR2
(53.3%x23.1%) and DR4 (40.0%x 14.8%). Concerning HLA-AB haplotypes, we observed a tendency for
increased frequency of HLA-A2B12 (16.6% x3.27%).
Discussion
The number of shared HLA haplotypes among 96
siblings with essential hypertension in 31 families
was significantly different from the number that
would be expected assuming the hypothesis of
independent transmission of HLA haplotypes and
essential hypertension. Thus, the present data support the notion that at least one of the genes
responsible for predisposition to essential hypertension is located within or very near the HLA complex. To our knowledge, the only other report on
linkage of HLA haplotypes and essential hypertension is the one by Heise et al.35 These authors
showed an excess of HLA haplotype sharing among
hypertensive individuals from three families, but
the data were not statistically significant.
In 15 (83.3%) of the 18 Caucasoid sibships analyzed (nine pairs, eight trios, and one quartet), we
observed that all the hypertensive siblings shared at
Gerbase-DeLima
et al
Essential Hypertension and HLA
607
TABLE 2. HLA Genotypes in Hypertensive Siblings From 31 Families
Negroid families
Caucasoid families
Fam no.
2
1
ac,bd
ac,ac
ac.ac
ad, ad
5
6
8
14
3
4
ad, ad
ac,ac
ac,ad
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bc,bc,ac
ac,ac,bc
ac,ac,ad
bc,ac,ac
ac,ad,ad
Genotypes
18
ac,bc,bd,bd,bc
aa\ac,bd,bd
ac,ac,ac,ac
bc,bc,bc,ac
9
12
13
16
27
10
ac, ad, ac
ad,ac,ac
Oriental family
Fam no.
be, be, ad
ad,bd,bc
ac,ac,ad,bc
ac,bd,ad,bd
7
11
ac,ac
26
15
17
21
22
23
28
29
30
25
ac,ac
ad,ac
31
ac,bd
19
20
24
Genotypes
Fam no.
Genotypes
ac,ac,ad,ac
bd,bc,bc,ac
ad,bc,bc,bc,bd,bc,bc
ac,ac,ac
ad,aa\ac,bc
a,b, paternal haplotypes; c,d, maternal haplotypes.
least one HLA haplotype. Sharing of two HLA
haplotypes was observed in six of nine sib pairs and
in two of eight sib trios. In five (41.7%) of the 12
Negroid sibships analyzed, we observed that all
hypertensive siblings shared at least one HLA haplotype. In one of two pairs, the siblings shared two
HLA haplotypes, and this was also the case in one
of three quartets of siblings. Although not all affected
siblings shared one HLA haplotype, in the other
seven Negroid families as well as in the Oriental
family studied, there was a tendency in several of
these families for the affected siblings to have HLA
haplotypes in common (Table 2).
The absence of a clear suggestion of linkage
between HLA and essential hypertension observed
in 11 of 31 of the families studied could be explained
by several possibilities, not mutually exclusive: 1)
high population frequency of the HLA-linked gene
for predisposition to essential hypertension, leading
TABLE 3. Statistical Analysis of HLA Haplotype Sharing in 96
Siblings with Essential Hypertension
Number of shared haplotypes
No. sibs/
family
No.
families
11
10
2
3
4
8
1
1
5
7
Total
31
Expected
Observed
Mean
Variance
16
29
36
11
5.5
25
34
6
10
97
6.1
10
86.1
3.75
1.75
0.11
0.031
11.14
Statistics: T=(97-0.5-86.1)/(11.14)" 2 =3.11595; p = l-4>
(3.11595), where <f> represents the standard normal integral;
/7=0.0OO9.
to parental sharing of this gene; 2) participation of
other genes for predisposition to essential hypertension located outside the HLA region; 3) dominance
of environmental factors. The idea that different
sets of genes leading to essential hypertension could
operate within different families has been already
put forward by Wright,36 and we suggest that the
heterogeneity of leading genes would tend to be
more pronounced among different ethnic groups.
Our data did not disclose a clear pattern (dominant vs. recessive) of inheritance of the HLA-linked
gene for predisposition to essential hypertension.
This is not surprising when the existence of other
genes outside the HLA region is considered, as well
as the role of environmental factors. Both of these
variables are candidates to interact with or influence the penetrance and expression of HLA-linked
genes. Penetrance is a statistical parameter that
refers to the proportion of individuals carrying a
genetic marker who display some form of the disease. Expression refers to the variable manifestations of such a gene. For instance, the degree of
expression of the HLA-linked gene for predisposition to essential hypertension could account for the
degree of severity and age at onset of hypertension.
We did not compare the distribution of HLA
haplotypes between hypertensive and normotensive siblings because this comparison is hampered
by factors such as incomplete penetrance, polygenic
character, environmental influences, and varying
age at onset of hypertension.
When we compared HLA haplotypic and antigenic frequency between the 18 probands of the
Caucasoid families and an ethnically matched local
control population, we observed a tendency to
608
Hypertension
Vol 14, No 6, December 1989
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increased frequency of the haplotype H1A-A2B12
(16.6% x3.27%) and of the antigens HLA-DR2
(53.3%x23.1%) and DR4 (40.0%x 14.8%). To our
knowledge, no study on HLA haplotype frequency in essential hypertension has been published. The only study29 in which HLA-DR antigen
frequency has been investigated reported a tendency to increased frequency of HLA-DR7. Formally, we were not entitled to analyze HLA
frequencies in the Negroid probands because their
number was too small (n = 12), and in addition, we
did not have a study of HLA frequencies in a local
Negroid control population. It is nevertheless interesting that the HLA haplotype A2B12 was present
in two of these probands (16.6%), whereas the
frequency of this haplotype in an international
Negroid population studied during the 9th International Histocompatibility Workshop37 was found
to be 2.99%. All the present findings of HLA
frequency in patients with essential hypertension
should be further investigated in a larger series of
patients before being considered as an indication
that certain specific HLA haplotypes or DR genes
may act as genetic markers for predisposition to
essential hypertension.
The long-term follow-up of blood pressure that is
being conducted in the HLA-typed normotensive
siblings from the families included in the present
study will certainly add important information concerning the predictive value of shared HLA haplotypes with hypertensive siblings in hypertension
development.
We believe that the importance of the present
study is not only the demonstration that one of the
genes predisposing to essential hypertension is
located within or very near the HLA complex, but
also because it discloses the possibility that, by
HLA typing, it might be possible to identify, among
siblings of a hypertensive individual, those with a
higher probability of later development of hypertension. In this context, HLA typing would represent a
marker allowing a better opportunity for prevention
and control of an important cardiovascular disease.
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KEY WORDS • essential hypertension • HLA haplotypes
immunogenetics • histocompatibility antigens
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Essential hypertension and histocompatibility antigens. A linkage study.
M Gerbase-DeLima, J J DeLima, L B Persoli, H B Silva, M Marcondes and G Bellotti
Hypertension. 1989;14:604-609
doi: 10.1161/01.HYP.14.6.604
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